1. Introduction
This invention relates to an emulsion composition for the formation of an artificial tear film over the ocular surface of the eye capable of providing mechanical lubrication while reducing evaporation of fluid. The composition is also useful for delivering medication to the ocular surface and for treating individuals wearing ocular prostheses such as contact lenses as the composition wets and provides lubrication for both the ocular surface and the surface of the prosthesis. More particularly, the invention relates to emulsion compositions capable of augmenting and maintaining a stable tear film over the ocular surface and/or delivering a medication to said surface without causing substantial blurring of vision nor discomfort. The emulsion is desirably in the form of a meta stable emulsion and is characterized by the use of a surfactant combination suitable for formation such an emulsion and maintaining the integrity of the emulsion during high temperature autoclaving.
2. Description of the Prior Art
It is known in the art that an aqueous tear film extends over the ocular surface and maintains the ocular surface moist and lubricated. It is also known that dehydration of moisture from the eye may result in discomfort. Further, it is known that compositions are available in the market intended for dry eye treatment. Commercially available compositions are primarily aqueous materials that supplement the tear film by adding a film of a water-soluble polymer over the surface of the eye. This film is short lived and provides limited relief.
The feeling of discomfort resulting from a dry eye condition may include ocular dryness, grittiness, burning, soreness or scratching, dependent upon the subject and the condition of the subject. Proposed causes for dry eye, treatment, and symptoms are described in a compendium of papers edited by Holly, The Preocular Tear Film in Health, Disease, and Contact Lens Wear, The Dry Eye Institute, Lubbock, Tex. 1986; edited by David A. Sullivan, Lacrimal Gland, Tear Film, and Dry Eye Syndromes, 1994, Plenum Press, New York; edited by David A. Sullivan et. al, Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2, 1998, Plenum Press, New York; edited by David A. Sullivan et. al, Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3, Part A and B, 2002, Kluwer Academic/Plenum Publishers, New York incorporated herein by reference for their teachings of the dry eye condition and the treatment thereof.
The most common treatment for dry eye involves temporary alleviation of dry eye symptoms by topical application of a tear substitute that adds a large volume of liquid to the anterior surface of the eye and related adnexa. Typical commercially available tear substitute compositions comprise water-soluble polymer solutions. Examples of such solutions include saline solutions of polyvinyl alcohol, hydroxypropylmethyl cellulose, or carboxymethyl cellulose. U.S. Pat. No. 4,421,748 teaches an artificial tear composition comprising an aqueous hypotonic solution of lecithin and a viscosity-adjusting agent such as a solution of a soluble cellulose.
Methods used to quantify the effectiveness of tear substitutes for dry eye treatment solutions have not been standardized, and many methods used to quantify the results obtained using such tear substitute compositions are often inaccurate. For this reason, it is known that reported relief of dry eye symptoms using known tear substitutes varies considerably from subject to subject, and regardless of the method used to quantify relief using a tear substitute, relief often does not exceed several minutes.
The symptoms associated with dry eye are often exacerbated with subjects using ocular prostheses such as contact lenses. In some cases, contact lens intolerance is caused in part, or in total, by the condition of dry eye and its symptoms. Further, the rate of evaporation from the eye is accelerated by the nature of the contact lens surface and the physical presence of the contact lens results in meniscii formation with additional physical and evaporative effects, even with subjects having an adequate tear film. For many subjects, contact lens intolerance is not overcome by topical application of tear substitutes. Therefore, there is a need for improved compositions and processes for treatment of the dry eye condition and for improving tolerance to ocular prostheses.
Improved compositions for dry eye treatment are disclosed in U.S. Pat. Nos. 4,914,088; 5,278,151; 5,294,607; 5,578,586, each incorporated herein by reference for its teaching of how to form an oil film over the surface of the eye including compositions used therefor. U.S. Pat. No. 4,914,088 teaches the use of certain charged phospholipids for the treatment of dry eye symptoms. The addition of a charged phospholipid to the eye is believed to assist in replicating the tear film that would naturally occur in the eye. In accordance with the patent, the phospholipid composition, preferably in the form of an aqueous emulsion, is topically applied to the eye where it is believed to disperse over the ocular surface and form a film that replicates a lipid layer that would be formed by the spreading of a naturally occurring lipid secreted principally from the meibomian glands during blinking. Because the phospholipid, when applied to the eye, in one embodiment, carries a net negative charge, it is believed that aligned molecules repel each other preventing complex aggregate formation thereby resulting in a stable phospholipid film. The patent theorizes that the film formed from the charged phospholipid assists in the formation of a barrier film reducing evaporation of the aqueous layer, thereby preserving the tear film. It is also now theorized that the phospholipid also functioned as a surfactant maintaining the emulsion stable.
The above referenced U.S. Pat. Nos. 5,278,151; 5,294,607; and 5,578,586 disclose further improvements in dry eye treatment. In accordance with the disclosure of said patents, the dry eye treatment composition of U.S. Pat. No. 4,914,088 is improved by the addition of an oil to the eye treatment composition, preferably a non-polar oil. The oil is added to improve the performance of a dry eye treatment composition by increasing the longevity of the tear film formed on the eye as a consequence of the formation of an oil film over the ocular surface that functions as an evaporation barrier—i.e, by providing and/or thickening the dehydration barrier (the oil layer) on the outer surface of the tear film. Thus, the oil increases the efficacy of the dry eye treatment solution and reduces performance variability from subject to subject.
A preferred embodiment disclosed in the above referenced patents is a dry eye treatment composition comprising a meta stable oil in water emulsion where the water phase includes the charged phospholipid believed to function both as an emulsifier and as a surfactant that assists in spreading of the oil over the eye to form a non-blurring film bonding of the oil to the ocular surface. Preferably, the oil phase comprises a non-polar oil. In accordance with this preferred embodiment, the emulsion is desirably “meta” stable so that when the emulsion is applied to the eye, it will rapidly break and spread over the ocular surface when it first comes into contact with the ocular surface, all as explained in the aforesaid patents.
The meta stable emulsions of the foregoing patents are formulated whereby the total amount of oil added to the eye preferably does not exceed 25 μl, more preferably varies between about 1 and 10 μl and most preferably varies between about 1 and 5 μl. If the amount of oil added to the eye is in excess of 25 μl, the oil layer on the surface of the eye may be of excessive thickness resulting in formation of oil globules on the surface of the eye. These globules are likely to result in prolonged blurring. To achieve control of the amount of oil added to the eye, the concentration limits of the oil in the emulsion are controlled within reasonable limits. An emulsion containing the oil in a concentration of at least 0.1 percent by weight of the total composition provides some benefits, a preferred concentration is at least 1.0 percent of the weight of the treatment composition, and the most preferred oil content varies between about 2.5 and 12.5 percent by weight of the emulsion.
Though the use of an oil in water meta stable emulsion having a negatively charged phospholipid as a surfactant provides excellent clinical results for dry eye treatment, there are certain disadvantages associated with their use. For example, the phospholipid component is costly when manufactured to the requirements and tolerances required for use on the eye. In addition, the storage of the phospholipids requires special conditions. Further, the lack of a long history relating to the use of a phospholipid on the eye could raise questions regarding safety and might create possible concerns by regulatory agencies that might require lengthy and costly clinical trials for approval. A further problem involves possible reluctance of companies marketing eye treatment products to deviate from the use of those ingredients having a long history of uneventful use in existing, commercially available treatment products.
For the foregoing reasons, it is desirable to find one or more surfactants that may be substituted for the charged phospholipids used to form a meta stable oil in water emulsion as disclosed in the aforesaid patents. Though it might appear that simple trial and error could be used to find a suitable surfactant, the task of finding a substitute surfactant is difficult. For example, the replacement surfactant must be acceptable for human use. Many available surfactants are not approved for use on the ocular surface. The replacement surfactant must not cause discomfort to the patient when used in a concentration adequate to form the desired emulsion. Many surfactants may not be added to the eye in suitable concentration without causing stinging. A physiologicall pH of between about 7.0 and 7.8 is required for application to the ocular surface. Many surfactants function as surfactants within a prescribed range of pH, both above and below pH 7. The desired emulsion for treatment of dry eye is preferably meta stable enabling it to rapidly break when applied to the eye. Therefore, the replacement surfactant must enable formation of an emulsion that is stable in manufacture and storage and meta stable and capable of breaking when applied to the ocular surface. The replacement surfactant must be capable of forming an emulsion containing oil in an acceptable concentration as described above to avoid prolonged blurring following application. Finally, the emulsion formed must be sufficiently robust to withstand sterilization at elevated temperatures without breaking, but sufficiently unstable so as to break when applied to the eye. It has been found that many replacement surfactants capable of forming a stable emulsion are incapable of maintaining stability of the emulsion during autoclaving at that temperature required for sterilization if used in a concentration suitable for addition to the eye without causing stinging, or in the alternative, if sufficient to withstand autoclaving, may be so robust that they will not break when applied to the eye.